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Project description:Rheumatoid arthritis (RA) is the most common systemic autoimmune disease. T helper 17 (Th17) cells are found in the inflamed synovium in RA and believed to play a pathogenic role. However, IL-17 targeted interventions have shown limited efficacy in established RA. Inflammation can induce Th17 transdifferentiation into IL-17 negative Th1 or Tr1 like exTh17. To assess the potential phenotype and role of exTh17 in inflammatory arthritis, we performed Th17 fate mapping studies in the SKG mouse model of RA. We generated triTh17-SKG (IL-17Cre.IfngYFP.Il10eGFP.R26tdTomfl.Zap70SKG) mice and leveraged them to show that in arthritic mice synovial Th17 transdifferentiate into IFNγ- and IL-10- exTh17 which become the most prominent CD4 population in chronic arthritis. These exTh17 cells are more arthritogenic than Th17, and able to sustain arthritis that is IL-17 independent but enriched with IL-6 and TNF, two known RA-promoting cytokines. Synovial exTh17 present a unique gene signature including upregulation of CD44 and S1PR4 that has correlates in the profile of CD4 T cells found in human RA synovium. We further demonstrate that a crosstalk with synoviocytes and S1P signaling promote Th17-exTh17 conversion and that CD44 – another known target for RA- is necessary for the arthritogenic effect of exTh17. Our study suggests that the synoviocyte expansion which occurs during RA progression can drive progressive conversion of Th17 into exTh17, which in turn sustain inflammation that has hallmarks of human established RA.
2026-03-25 | GSE232734 | GEO
Project description:T helper 17 (Th17) cells are found in peripheral blood and synovial fluid of rheumatoid arthritis (RA) patients, however IL-17-targeted interventions have shown limited efficacy in established RA. While it is known that inflammation can induce Th17 transdifferentiation into Th1- or Tr1-like IL-17-negative exTh17 cells, the role of exTh17 in arthritis is not known. Here, we explore the premise that exTh17 cells promote joint inflammation in autoimmune arthritis. To assess the potential immunophenotypic dynamics and role of exTh17 in inflammatory arthritis, we performed Th17 lineage tracing studies in the SKG mouse model of RA. We show that in arthritic mice, synovial Th17 transdifferentiate into IFNγ- and IL-10- exTh17 which become the most prominent CD4+ population in chronic arthritis. SKG exTh17 cells are more arthritogenic than Th17, and able to sustain synovial inflammation that is IL-17-independent but enriched with IL-6 and TNF, two RA-promoting cytokines. Synovial exTh17 present a unique gene signature, including upregulation of CD44 and S1PR4. This gene signature has correlates in the profile of CD4+ T cells found in human RA synovium. We further demonstrate that crosstalk between Th17 and fibroblast-like synoviocytes via S1P signaling promote Th17-exTh17 conversion. Additionally, CD44 is necessary for the arthritogenic effect of exTh17. Our study suggests that the fibroblast-like synoviocyte expansion, which occurs during RA progression, can drive progressive conversion of Th17 into exTh17 which sustains inflammation with features of human established RA. The results offer new insights that could be potentially useful for future precision therapy approaches to RA.
2026-03-25 | GSE293970 | GEO
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234597 | GEO
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234596 | GEO
Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
2025-09-19 | GSE234595 | GEO
Project description:Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death.
| S-EPMC11799179 | biostudies-literature
Project description:TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis
| PRJNA982107 | ENA
Project description:TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis
| PRJNA982108 | ENA
Project description:TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis
| PRJNA982104 | ENA
Project description:BACKGROUND:Role of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently. However, their involvement in human rheumatoid arthritis (RA) is not conclusive. Pathogenesis of RA is complex and involves various T cell subsets and neutrophils. Here, we aimed at understanding the impact of IL-9 on infiltrating immune cells and their eventual role in synovial inflammation in RA. METHODS:In vitro stimulation of T cells was performed by engagement of anti-CD3 and anti-CD28 monoclonal antibodies. Flow cytometry was employed for measuring intracellular cytokine, RORγt in T cells, evaluating apoptosis of neutrophils. ELISA was used for measuring soluble cytokine, Western blot analysis and confocal microscopy were used for STAT3 phosphorylation and nuclear translocation. RESULTS:We demonstrated synovial enrichment of Th9 cells and their positive correlation with disease activity (DAS28-ESR) in RA. Synovial IL-9 prolonged the survival of neutrophils, increased their matrix metalloprotienase-9 production and facilitated Th17 cell differentiation evidenced by induction of transcription factor RORγt and STAT3 phosphorylation. IL-9 also augmented the function of IFN-γ + and TNF-α + synovial T cells. CONCLUSIONS:We provide evidences for critical role of IL-9 in disease pathogenesis and propose that targeting IL-9 may be an effective strategy to ameliorate synovial inflammation in RA. Inhibiting IL-9 may have wider impact on the production of pathogenic cytokines involved in autoimmune diseases including RA and may offer better control over the disease.
| S-EPMC5791733 | biostudies-literature